Metabolic syndrome (MS) is a cluster of risk factors that predispose to major cardiovascular diseases and its complications, determining liver and kidney impairment. In the last decade, the indications to transplantation are increasing, with a linear incidence of the complications of the procedure. MS represents one of the commonest, being in turn may the consequence of the underlying disease that required the transplantation, or the result of the medical treatment, as well as one of the most important factor influencing the morbidity and mortality of the transplanted patients. Due to the growing incidence of the MS in these patients, it is crucial to focus and clarify the leading causes determining the onset of the metabolic disarrangement, its outcome and the hypothetical mechanism through which the clinicians could reduce the impact of the disease. In fact, prevention, early recognition, and treatment of the factor that could predict the onset or progression of the MS after the transplantation may impact long term survival of patients, that is again the scope of the same transplant. This review will update the different mechanisMS of the pathogenesis of MS in this population, the clinical effects of the presence of the MS, observing the risk factors to be treated before and after the transplantation and suggesting the management of the follow-up.
One of the critical points in the pathogenesis of aortic aneurysms (AAs) is the disruption of the balance between vascular extracellular matrix (ECM) deposition and degradation. AAs are common features in some genetically determined diseases of the connective tissue, such as Marfan and Ehlers-Danlos. Acquired factors determining an enhanced inflammatory state of the arterial wall also play a key role. Previous studies have determined the role of tumor growth factor β (TGF-β); as a principal mediator of the pathogenesis of the alterations of the arterial wall homeostasis in AAs. The medical management of any AA is mainly focused on the use of pharmacological agents that reduce hemodynamic stress of the aortic wall, since hypertension is the major risk factor for the enlargement and rupture of the AAs. However, this is far from being a comprehensive pathophysiology-based therapeutic approach. Drugs potentially able to reduce the release of TGF-β may play a role in the pathogenesis of the AAs. They work by improving matrix repair, decreasing the proteolytic pattern and inhibition of angiotensin-converting enzyme (ACE) as well as preventing angiotensin II-induced angiotensin type-1 receptor (AT1R) activation. A new pathophysiology-based therapeutic approach, involving the mechanisms leading to the rupture of the AAs, could represent an additional tool in combination with the current established antihypertensive therapy.
Enhanced oxidative stress contributes to the pathogenesis of diabetes and its complications. Peroxiredoxin 6 (PRDX6) is a key regulator of cellular redox balance, with the peculiar ability to neutralize peroxides, peroxynitrite, and phospholipid hydroperoxides. In the current study, we aimed to define the role of PRDX6 in the pathophysiology of type 2 diabetes (T2D) using PRDX6 knockout (−/−) mice. Glucose and insulin responses were evaluated respectively by intraperitoneal glucose and insulin tolerance tests. Peripheral insulin sensitivity was analyzed by euglycemic-hyperinsulinemic clamp, and molecular tools were used to investigate insulin signaling. Moreover, inflammatory and lipid parameters were evaluated. We demonstrated that PRDX6−/− mice developed a phenotype similar to early-stage T2D caused by both reduced glucose-dependent insulin secretion and increased insulin resistance. Impaired insulin signaling was present in PRDX6−/− mice, leading to reduction of muscle glucose uptake. Morphological and ultrastructural changes were observed in islets of Langerhans and livers of mutant animals, as well as altered plasma lipid profiles and inflammatory parameters. In conclusion, we demonstrated that PRDX6 is a key mediator of overt hyperglycemia in T2D glucose metabolism, opening new perspectives for targeted therapeutic strategies in diabetes care.
The aetiology of aortic aneurysms (AAs) is the subject of intense clinical investigation. One of the critical points in their pathogenesis is the disruption of the balance between vascular extracellular matrix deposition and degradation. AAs are common features in some genetically determined diseases of the connective tissue, such as Marfan and Loeys-Dietz Syndromes. Acquired factors determining an enhanced inflammatory state of the arterial wall also play a key role. Previous studies have determined the role of TGF-β as the principal mediator of the pathogenesis of the alterations of the arterial wall homeostasis in aneurysms.
The current medical management of any AA is mainly focused on the use of pharmacological agents that reduce hemodynamic stress of aortic wall, since hypertension is the major risk factor for the enlargement and rupture of the AAs. Thus, this approach is useful to reduce the risk of aneurysm rupture but is far from being a comprehensive pathophysiology-based therapeutic approach. Drugs with the potential of reducing the action of TGF-β, which activation and expression has been reported to have a major role in the molecular pathogenesis of the aneurysms, improving matrix repair, decreasing the proteolytic pattern and inhibition of angiotensin converting enzyme as well as preventing angiotensin II-induced AT1R (angiotensin type 1 receptor) activation, can represent new options in the medical therapy of AAs. We propose that a combination of statins and PPAR-γ agonist could be a useful adjunctive therapy in this condition. The new pathophysiology-based therapeutic approach, involving the pathological patterns and mechanisms leading to the rupture of the AAs, could represent an interesting additional tool in combination with the current established anti-hypertensive therapy.
The prevalence of hypovitaminosis D is high among obese subjects. Further, low 25-hydroxyvitamin D (25(OH)D) concentration has been postulated to be a risk factor for type 2 diabetes, although its relation with insulin-sensitivity is not well investigated. Thus, we aimed to investigate the relationship between 25(OH)D concentration and insulinsensitivity, using the glucose clamp technique. In total, 39 subjects with no known history of diabetes mellitus were recruited.
The association of 25(OH)D concentration with insulin-sensitivity was evaluated by hyperinsulinemic euglycemic clamp. Subjects with low 25(OH)D (<50nmol/l) had higher BMI (P = 0.048), parathyroid hormone (PTH) (P = 0.040), total cholesterol (P = 0.012), low-density lipoprotein (LDL) cholesterol (P = 0.044), triglycerides (P = 0.048), and lower insulin-sensitivity as evaluated by clamp study (P = 0.047). There was significant correlation between 25(OH)D and BMI (r = −0.58; P = 0.01), PTH (r = −0.44; P < 0.01), insulin sensitivity (r = 0.43; P < 0.01), total (r = −0.34; P = 0.030) and LDL (r = −0.40; P = 0.023) (but not high-density lipoprotein (HDL)) cholesterol, and triglycerides (r = 0.45; P = 0.01).
Multivariate analysis using 25(OH)D concentration, BMI, insulin-sensitivity, HDL cholesterol, LDL cholesterol, total cholesterol, and triglycerides, as the cofactors was performed. BMI was found to be the most powerful predictor of 25(OH)D concentration (r = −0.52; P < 0.01), whereas insulin-sensitivity was not significant. Our study suggested that there is no cause–effect relationship between vitamin D and insulin-sensitivity. In obesity, both low 25(OH)D concentration and insulin-resistance appear to be dependent on the increased body size.